Identification of ASK1 inhibitors among the derivatives of Benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one

We have identified novel chemical class of ASK1 inhibitors, namely Benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one, using molecular modeling techniques. It was found that the most active compound 1-(6-Fluoro-benzothiazol-2-yl)-3-hydroxy-5-[3-(3-methyl-butoxy)-phenyl]-4-(2-methyl-2,3-dihydro-benzofuran-5-carbonyl)-1,5-dihydro-pyrrol-2-one (BPyO-34) inhibits ASK1 with IC50 of 0.52 μM in vitro in kinase assay. The structure-activity relationships of 34 derivatives of Benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one have been studied and binding mode of this chemical class has been proposed (Fig. 1).

Figure 1. The binding mode of BPyO-34 in the active site of the ASK1 catalytic subunit. Hydrogen bonds are shown by the green dotted lines and sulfur-π interaction is presented by the yellow dotted line.

It was revealed that the presence of benzothiazole in the structure of tested compounds is very significant for the inhibitory activity toward ASK1. Accordingly to the in silico modeling results this heterocycle is involved in hydrophobic interactions with adenine-binding region of ASK1 ATP-binding site and forms sulfur-π interaction with Val757 located in the hinge region. Also, it was shown, that the structure of substituent which interacts with hydrophobic pocket I is important for compound inhibitory activity toward ASK1.

The most active derivatives of Benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one which posses submicromolar inhibitory activity toward ASK1 can be used for biological experiments.